The manner in which chemicals or drugs are administered has gained increasing attention in the past two decades. Normally, a chemical is administered in a high dose at a given time only to have to repeat that dose several hours or days later. This is not economical and sometimes results in damaging side effects. As a consequence, increasing attention has been focused on methods of giving drugs continually for prolonged time periods and in a controlled fashion. Controlled or sustained release dosage forms provide a therapeutic dose of the drug soon after administration, and then gradually release the drug over an extended period of time. The primary method of accomplishing this controlled release has been through incorporating the drugs within polymers or to surround or encapsulate a core comprising the drug with a polymer coat. Depending on the type and amount of drug, as well as the type and amount of polymer and other pharmaceutically acceptable excipients the desired controlled release profile can be obtained.
The majority of polymers used to develop coatings for controlled release dosage forms are hydrophobic and can be applied either dry, from a solution, or suspension. As most of these polymers are poorly soluble in water, they are usually applied by dissolving the polymer in an organic solvent and then sprayed onto the drug core and evaporating off the solvent. The use of organic solvents, however, is considered problematic for several reasons. The most obvious reason relates to the safety hazards associated with the use of organic solvents. Organic solvents in general are highly flammable and carcinogenic. Further, organic solvents are expensive and the storage, disposal and use of organic solvents raise environmental concerns. Accordingly, it would be desirable to prepare aqueous suspensions or solutions of controlled release coatings comprising hydrophobic polymers suitable for coating a wide variety of drug cores wherein the use of organic solvents is not required.
Eudragit® NE30D, which contains 30% solids, is one of the first aqueous polymeric dispersions used for coating pharmaceutical dosage forms. Eudragit® NE30D has many advantages over other polymers for use as a film former for obtaining a controlled release drug profile and is suited for controlled or sustained release drug formulations. The polymer forms a soft, flexible film at room temperature without any plasticizer. Also, no reactions or absorptive effects are observed when the polymer comes in direct contact with a therapeutically active agent. It is prepared by emulsion polymerization and contains neutral copolymers of ethyl acrylate-methyl methacylate esters that are insoluble over the entire physiological pH range but will still swell in water and give permeable membranes, The permeability is independent of pH and is thus suitable for the development of pH-independent modified-release oral dosage forms, provided that the solubility of the drug is also pH-independent.
One of the differences between aqueous polymeric solutions and dispersions is the role water plays during film formation. In solutions, water is a solvent and drying is accompanied by an excessive increase in viscosity, which in turn suppresses the rate of evaporation. Excess energy is therefore required to drive off the water. In contrast, in polymeric dispersions such as Eudragit® NE30D, water is only a dispersion medium and does not solvate the polymers. Consequently, less heat is needed to evaporate the water. Fast water evaporation coupled with the high solids content of the dispersion reduces processing time. These properties are even more relevant when dealing with highly water-soluble or moisture sensitive therapeutically active agents.
The pigment binding capacity of Eudragit® NE30D is very high, so that up to about 2-3 parts by weight of additives can be incorporated into 1 part by weight of dry polymer without affecting the film properties. The polymer is also compatible with a wide variety of pharmaceutical excipients.
Plasticizers are generally added to coating formulations to modify the physical properties i.e., the glass transition temperature (Tg) of the polymer to make it more usable. The Tg is the temperature at which an amorphous polymer (or the amorphous regions in a partially crystalline polymer) changes from a hard and relatively brittle condition to a viscous or rubbery condition. Plasticizers function by decreasing the Tg of the polymer so that under ambient conditions the films are softer, more pliable and often stronger, and thus better able to resist mechanical stress. Eudragit® NE30D, however, has a low Tg and accordingly does not require the use of plasticizers. In fact, addition of plasticizers can be detrimental as it can increase the viscosity of the Eudragit® NE30D formulation and negate one of the distinct advantages of the dispersion over the polymeric solution. Incorporation of plasticizers into Eudragit® NE30D formulations can also increase the tackiness of the coat and complicate the coating process.
Due to its low Tg, Eudragit® NE30D is known to be sensitive to excessive drying conditions or exposure to high temperatures. Prior art teachings state that excessive drying of Eudragit® NE30D coats can be detrimental as such conditions do not allow the coating formulation to spread out evenly and promote particle deformation and coalescence. For example, see Ghebre-Sellassie and Nesbit, Application of Eudragit E30D in Controlled-Release Coatings in Aqueous Polymeric Coatings for Pharmaceutical Forms, J. McGinity Ed., 1989, Marcel Dekker, Inc., pp 247-266. Also, it is known that during the coating process, the product temperature should be kept at around 26° C. If the product temperature is very high, the coating material becomes tacky owing to the low Tg of Eudragit® NE30D, which can lead to agglomeration of the coated product. The prior art teachings also state that Eudragit® NE30D coated products should not be stored at temperatures above 40° C., as stability tests conducted at elevated temperatures may not correlate with the long-term behavior of Eudragit® NE30D coated products at room temperature.
Attempts have been made in the prior art to design aqueous polymer coatings suitable for use on drug cores to obtain controlled or sustained release profiles using the Eudragit® polymers, and in particular Eudragit® NE30D
It would seem that although the prior art teaches the use of aqueous acrylic dispersion coatings of Eudragit® polymers such as Eudragit® NE30D, in most part, the prior art does not seem to have overcome long term stability problems of products coated with aqueous Eudragit® NE30D dispersions. Where the products have been found to be stable, the length of curing is very long and this is inefficient to the manufacturing process and also raises problems with storage of scale-up product. Accordingly, and given the advantages and versatility of aqueous polymeric dispersion coatings such as those using Eudragit® NE30D, it would be desirable that a stable controlled or sustained release coat be developed with short curing times to enhance process times.